WO2021162054A1 - Inhibiteur de l'activité du récepteur de la ryanodine de type 2 - Google Patents

Inhibiteur de l'activité du récepteur de la ryanodine de type 2 Download PDF

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WO2021162054A1
WO2021162054A1 PCT/JP2021/005044 JP2021005044W WO2021162054A1 WO 2021162054 A1 WO2021162054 A1 WO 2021162054A1 JP 2021005044 W JP2021005044 W JP 2021005044W WO 2021162054 A1 WO2021162054 A1 WO 2021162054A1
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carbon atoms
group
substituted
ring
unsubstituted
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PCT/JP2021/005044
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Japanese (ja)
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なごみ 呉林 國廣
尚 村山
影近　弘之
修一 森
磨里 湯浅
大翔 飯沼
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学校法人順天堂
国立大学法人東京医科歯科大学
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Priority to JP2022500452A priority Critical patent/JPWO2021162054A1/ja
Priority to EP21753994.9A priority patent/EP4104835A4/fr
Priority to US17/760,419 priority patent/US20230150952A1/en
Publication of WO2021162054A1 publication Critical patent/WO2021162054A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a type 2 ryanodine receptor activity inhibitor. More specifically, the present invention relates to a type 2 ryanodine receptor activity inhibitor, a drug, a tetrazole compound, and the like.
  • the ryanodine receptor is a Ca 2+ release channel responsible for the release of calcium ions (Ca 2+ ) from the sarcoplasmic reticulum (SR), an essential step for muscle contraction.
  • RyR is stimulated by Ca 2+ on the cytosol side to release Ca 2+ into the cytosol (Ca 2+ -induced Ca 2+ release, CICR). Therefore, it acts as a positive feedback mechanism, and a small amount of Ca 2+ in the cytosol near the channel causes more Ca 2+ release from SR.
  • RyR is mainly RyR1 (type 1 ryanodine receptor) expressed in skeletal muscle, RyR2 (type 2 ryanodine receptor) mainly expressed in myocardium, and RyR3 (type 3 ryanodine receptor) expressed in large amounts in the brain. It has been found by the studies of the present inventors that a specific quinoline-3-carboxylic acid derivative has an effect of suppressing the activity of RyR1 among the above (Patent Document 1). , RyR2 activity inhibitor has not been found yet.
  • RyR2 gene mutations abnormally enhance CICR activity, including catecholamine-induced polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, arrhythmogenic right ventricular cardiomyopathy, left ventricular densification disorder, epilepsy, and mental retardation.
  • an abnormal increase in RyR2 due to excessive phosphorylation or the like causes chronic heart failure, Alzheimer's disease, etc. (for example, Non-Patent Documents 1 to 6 and the like). Therefore, it is desired to develop a RyR2 activity inhibitor having an excellent RyR2 activity inhibitory effect. Therefore, an object of the present invention is to provide a RyR2 activity inhibitor having an excellent RyR2 activity inhibitory effect.
  • the present inventors cultivate cultured cells expressing a fluorescent endoplasmic reticulum Ca 2+ indicator and a disease mutant RyR, and cultured cells expressing a fluorescent endoplasmic reticulum Ca 2+ indicator and a wild-type RyR, respectively, and test them.
  • a disease associated with abnormal enhancement of CICR activity inhibitor that is, ryanodine receptor activity. It was found that a prophylactic or therapeutic drug for the above could be screened (Non-Patent Document 7), and a patent application was filed earlier (Japanese Patent Application No. 2016-113147).
  • the specific compound has an excellent effect of suppressing RyR2 activity, and a prophylactic or therapeutic agent for a disease related to abnormal enhancement of RyR2 activity.
  • the present invention was completed by finding that it is useful as a compound.
  • the present invention provides the following ⁇ 1> to ⁇ 12>.
  • Type 2 ryanodine receptor activity containing a compound represented by the following formula ( ⁇ 1), a salt thereof, or a solvate thereof hereinafter, these may be collectively referred to as “compound ( ⁇ 1)”.
  • Inhibitor hereinafter, also referred to as type 2 ryanodine receptor activity inhibitor of the present invention, RyR2 activity inhibitor of the present invention.
  • Ring Q 1 and ring Q 2 are each, independently, condensed with monocyclic heterocycle or monocyclic carbocyclic ring and a benzene ring, or represents a benzene ring, R 1 and R 2 are independently substituted or unsubstituted hydrocarbon groups having 1 to 8 carbon atoms, substituted or unsubstituted alkoxy groups having 1 to 8 carbon atoms, and substituted or unsubstituted carbon atoms 2 to 8 respectively.
  • R 3 represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms.
  • R 4 represents a divalent hydrocarbon group having 1 to 8 carbon atoms.
  • X represents an oxygen atom or a sulfur atom
  • Y represents a methine group or a nitrogen atom
  • n and m each independently represent an integer of 0 to 5.
  • n R 1s may be the same or different, and the two R 1s may be combined to form a ring.
  • m R 2s may be the same or different, and the two R 2s may be combined to form a ring.
  • ring Q 1 and the ring Q 2 are independently fused rings of a 4- to 8-membered oxygen-containing monocyclic heterocycle and a benzene ring, or a benzene ring.
  • R 1 and R 2 are independently substituted or unsubstituted alkyl groups having 1 to 8 carbon atoms, substituted or unsubstituted alkoxy groups having 2 to 8 carbon atoms, and substituted or unsubstituted carbon atoms.
  • the type 2 lianodine receptor activity according to ⁇ 1> or ⁇ 2> which is an alkoxy group of 1 to 8, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a hydroxy group, a cyano group, or a halogen atom.
  • Inhibitor. ⁇ 4> The type 2 ryanodine receptor activity inhibitor according to any one of ⁇ 1> to ⁇ 3>, wherein R 4 is an alkanediyl group having 1 to 8 carbon atoms or an arcendyl group having 2 to 8 carbon atoms. ..
  • ⁇ 5> Any of ⁇ 1> to ⁇ 4>, wherein R 3 is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms, or a substituted or unsubstituted alkenyl group having 2 to 8 carbon atoms.
  • ⁇ 6> The type 2 ryanodine receptor activity inhibitor according to any one of ⁇ 1> to ⁇ 5>, wherein R 3 is a methyl group.
  • ⁇ 7> The type 2 ryanodine receptor activity inhibitor according to any one of ⁇ 1> to ⁇ 6>, wherein n is an integer of 1 to 5.
  • ⁇ 8> The type 2 ryanodine receptor activity inhibitor according to any one of ⁇ 1> to ⁇ 7>, wherein m is an integer of 1 to 5.
  • a drug for preventing or treating a disease related to abnormally enhanced type 2 ryanodine receptor activity which contains a compound represented by the above formula ( ⁇ 1) or a salt thereof or a solvate thereof (hereinafter referred to as the present invention). Also referred to as the drug of invention).
  • Diseases associated with abnormal hyperactivity of type 2 lianozin receptor are catecholamine-induced polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, arrhythmogenic right ventricular cardiomyopathy, left ventricular densification disorder, epilepsy, The medicament according to ⁇ 9>, which is a disease selected from mental retardation, chronic heart failure and Alzheimer's disease.
  • Ring Q 1 and ring Q 2 are each, independently, condensed with monocyclic heterocycle or monocyclic carbocyclic ring and a benzene ring, or represents a benzene ring, R 1 and R 2 are independently substituted or unsubstituted hydrocarbon groups having 1 to 8 carbon atoms, substituted or unsubstituted alkoxy groups having 1 to 8 carbon atoms, and substituted or unsubstituted carbon atoms 2 to 8 respectively.
  • R 3 represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms.
  • R 4 represents a divalent hydrocarbon group having 1 to 8 carbon atoms.
  • X represents an oxygen atom or a sulfur atom
  • Y represents a methine group or a nitrogen atom
  • n and m each independently represent an integer of 1 to 5.
  • n R 1s may be the same or different, and the two R 1s may be combined to form a ring.
  • m R 2s may be the same or different, and the two R 2s may be combined to form a ring.
  • ⁇ 13> Use of a compound represented by the above formula ( ⁇ 1), a salt thereof, or a solvate thereof for producing a type 2 ryanodine receptor activity inhibitor.
  • ⁇ 14> Use of the compound represented by the above formula ( ⁇ 1), a salt thereof, or a solvate thereof for the production of a drug for the prevention or treatment of a disease associated with abnormal enhancement of type 2 ryanodine receptor activity.
  • .. ⁇ 15> A compound represented by the above formula ( ⁇ 1), a salt thereof, or a solvate thereof for use in suppressing type 2 ryanodine receptor activity.
  • ⁇ 16> A compound represented by the above formula ( ⁇ 1), a salt thereof, or a solvate thereof for use in the prevention or treatment of diseases associated with abnormally enhanced type 2 ryanodine receptor activity.
  • ⁇ 17> Use of a compound represented by the above formula ( ⁇ 1), a salt thereof, or a solvate thereof for suppressing the type 2 ryanodine receptor activity.
  • ⁇ 18> Use of a compound represented by the above formula ( ⁇ 1), a salt thereof, or a solvate thereof for preventing or treating a disease associated with abnormally enhanced type 2 ryanodine receptor activity.
  • a method for suppressing type 2 ryanodine receptor activity which comprises a step of administering a compound represented by the above formula ( ⁇ 1), a salt thereof, or a solvate thereof.
  • a method for preventing or treating a disease related to abnormal enhancement of type 2 ryanodine receptor activity which comprises a step of administering a compound represented by the above formula ( ⁇ 1), a salt thereof, or a solvate thereof.
  • the compound represented by the formula ( ⁇ 1), a salt thereof, or a solvate thereof has an excellent effect of suppressing RyR2 activity, and is useful as a prophylactic or therapeutic agent for diseases associated with abnormal enhancement of RyR2 activity. Further, the compounds ( ⁇ 2) to ( ⁇ 12) of the present invention are novel compounds having an excellent effect of suppressing RyR2 activity.
  • Electrocardiogram of RyR2 mutation-introduced mice before and after administration of compound 57 The figure which shows the effect of compound 57 on the occurrence of arrhythmia in normal times of RyR2 mutation-introduced mouse.
  • the type 2 ryanodine receptor activity inhibitor and the drug of the present invention contain a compound represented by the following formula ( ⁇ 1), a salt thereof, or a solvate thereof.
  • a compound represented by the formula ( ⁇ 1) or a salt thereof or a solvate thereof has an inhibitory effect on RyR2 activity and that it is useful as a prophylactic or therapeutic agent for diseases related to abnormal enhancement of RyR2 activity.
  • "prevention or treatment" of a disease shall include use for both prevention and treatment of a disease in addition to prevention and treatment of a disease.
  • Ring Q 1 and ring Q 2 are each, independently, condensed with monocyclic heterocycle or monocyclic carbocyclic ring and a benzene ring, or represents a benzene ring, R 1 and R 2 are independently substituted or unsubstituted hydrocarbon groups having 1 to 8 carbon atoms, substituted or unsubstituted alkoxy groups having 1 to 8 carbon atoms, and substituted or unsubstituted carbon atoms 2 to 8 respectively.
  • R 3 represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms.
  • R 4 represents a divalent hydrocarbon group having 1 to 8 carbon atoms.
  • X represents an oxygen atom or a sulfur atom
  • Y represents a methine group or a nitrogen atom
  • n and m each independently represent an integer of 0 to 5.
  • n R 1s may be the same or different, and the two R 1s may be combined to form a ring.
  • m R 2s may be the same or different, and the two R 2s may be combined to form a ring.
  • Y represents a methine group or a nitrogen atom, and a nitrogen atom is preferable from the viewpoint of the effect of suppressing RyR2 activity.
  • the ring Q 1 and ring Q 2 are respectively independently, condensed with monocyclic heterocycle or monocyclic carbocyclic ring and a benzene ring, or a benzene ring.
  • the monocyclic heterocycle a 4- to 8-membered monocyclic heterocycle is preferable, a 5- to 7-membered monocyclic heterocycle is more preferable, and a 5- to 6-membered monocyclic heterocycle is particularly preferable.
  • examples of the monocyclic heterocycle include a monocyclic heterocycle containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the oxygen-containing monocyclic heterocycle is used.
  • a 4- to 8-membered oxygen-containing monocyclic heterocycle is more preferred.
  • the monocyclic heterocycle include an oxetane ring, a dioxolane ring, a dioxane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a tetrahydrothiophene ring, a tetrahydrothiophene ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring and the like. ..
  • an oxetane ring, a dioxolane ring, and a dioxane ring are preferable.
  • Specific examples of the fused ring between the monocyclic heterocycle and the benzene ring include 7-oxabicyclo [4.2.0] octa-1 (6), 2,4-triene ring, and 1,3-benzo. Examples thereof include a dioxol ring and a 1,4-benzodioxan ring.
  • the monocyclic carbon ring a 4- to 8-membered monocyclic carbon ring is preferable, and a 5- to 7-membered monocyclic carbon ring is more preferable.
  • the fused ring between the monocyclic carbon ring and the benzene ring include an indane ring and a tetralin ring.
  • the bond site between Y and the adjacent carbon atom in the formulas ( ⁇ 1) and ( ⁇ 2) is particularly high. It is not limited, and may be a monocyclic heterocycle, a monocyclic carbocycle, or a benzene ring contained in the condensed ring, but a benzene ring contained in the condensed ring is preferable.
  • the bonding site between R 3 and the adjacent nitrogen atom in the formulas ( ⁇ 1) and ( ⁇ 2) is particularly limited. It may be a monocyclic heterocycle, a monocyclic carbocycle or a benzene ring contained in the condensed ring, but a benzene ring contained in the condensed ring is preferable.
  • Ring Q 1 as the ring Q 2, from the viewpoint of RyR2 activity inhibiting effect, condensed with monocyclic heterocycle with a benzene ring, a benzene ring are preferred, 4-8 membered oxygen-containing monocyclic heterocyclic ring and a benzene ring A fused ring with and a benzene ring are more preferable.
  • a benzene ring is particularly preferred.
  • 1,3-benzodioxole ring and benzene ring are particularly preferable from the viewpoint of the effect of suppressing RyR2 activity.
  • R 1 and R 2 are independently substituted or unsubstituted hydrocarbon groups having 1 to 8 carbon atoms and substituted or unsubstituted alkoxy groups having 1 to 8 carbon atoms, respectively. , Substituent or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, substituted or unsubstituted alkanoyl group having 2 to 8 carbon atoms, substituted or unsubstituted alkanoyloxy group having 2 to 8 carbon atoms, hydroxy group, cyano group. , Or a halogen atom. Further, in the formulas ( ⁇ 1) and ( ⁇ 2), R 3 represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms.
  • the "hydrocarbon group” represented by R 1 , R 2 and R 3 is a concept including an aliphatic hydrocarbon group, an alicyclic hydrocarbon group and an aromatic hydrocarbon group, but the aliphatic hydrocarbon group is used. preferable.
  • the aliphatic hydrocarbon group may be linear or branched chain, and may be saturated or unsaturated.
  • Examples of the aliphatic hydrocarbon group include an alkyl group, an alkenyl group and an alkynyl group. Among these, an alkyl group and an alkenyl group are preferable, and an alkyl group is more preferable, from the viewpoint of the effect of suppressing RyR2 activity.
  • the number of carbon atoms of the alkyl group is preferably 1 to 8, more preferably 1 to 4, still more preferably 1 to 3, and particularly preferably 1 from the viewpoint of the effect of suppressing RyR2 activity.
  • the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group and the like.
  • a methyl group, an ethyl group, an n-propyl group and an isopropyl group are preferable, and a methyl group is particularly preferable, from the viewpoint of the effect of suppressing RyR2 activity.
  • the carbon number of the alkenyl group and the alkynyl group is preferably 2 to 8, more preferably 2 to 4, and particularly preferably 2 to 3.
  • alkenyl group examples include an ethenyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group, a 1,3-butadienyl group, a 1-pentenyl group, a 2-pentenyl group and a 1-hexenyl group.
  • the group etc. can be mentioned.
  • alkynyl group examples include an ethynyl group, a 1-propynyl group, a 1-butynyl group, a 1-pentynyl group, a 3-pentynyl group, a 1-hexynyl group and the like.
  • the "hydrocarbon group" represented by R 1 , R 2 and R 3 may or may not have a substituent.
  • substituents include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, hydroxy group and cyano group.
  • the substitution position and the number of substitutions of the substituents are arbitrary, and when two or more substituents are present, the substituents may be the same or different.
  • a haloalkyl group such as a trifluoromethyl group, a pentafluoroethyl group or a 2,2,2-trifluoroethyl group is preferable from the viewpoint of the effect of suppressing RyR2 activity.
  • the carbon number of the "alkoxy group" represented by R 1 and R 2 is preferably 1 to 6, more preferably 1 to 3, and particularly preferably 1 from the viewpoint of the effect of suppressing RyR2 activity.
  • the alkoxy group may be linear or branched chain.
  • a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a butoxy group, a pentyloxy group, a hexyloxy group and the like can be mentioned.
  • the "alkoxy group” represented by R 1 and R 2 may or may not have a substituent. Examples of the substituent include those similar to those that the hydrocarbon group may have.
  • the substitution position and the number of substitutions of the substituents are arbitrary, and when two or more substituents are present, the substituents may be the same or different.
  • the alkoxy group having a substituent include a haloalkoxy group such as a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a pentafluoroethoxy group, and a 2,2,2-trifluoroethoxy group from the viewpoint of suppressing RyR2 activity. Is preferable.
  • the number of carbon atoms of the alkoxycarbonyl group, alkanoyl group, and alkanoyloxy group represented by R 1 and R 2 is preferably 2 to 6, more preferably 2 to 4, from the viewpoint of the effect of suppressing RyR2 activity.
  • the alkoxycarbonyl group, alkanoyl group and alkanoyloxy group may be linear or branched chain.
  • the alkoxycarbonyl group, alkanoyl group and alkanoyloxy group is preferable from the viewpoint of the effect of suppressing RyR2 activity.
  • Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propyloxycarbonyl group, an isopropyloxycarbonyl group, an n-butoxycarbonyl group, a tert-butoxycarbonyl group and the like.
  • Examples of the alkanoyl group include an acetyl group and a propionyl group.
  • Examples of the alkanoyloxy group include an acetoxy group and a propanoyloxy group.
  • Examples of the substituent which the alkoxycarbonyl group, the alkanoyl group and the alkanoyloxy group may have include the same as those which the hydrocarbon group may have.
  • the substitution position and the number of substitutions of the substituents are arbitrary, and when two or more substituents are present, the substituents may be the same or different.
  • halogen atom represented by R 1 and R 2 examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Of these, a fluorine atom is preferred.
  • R 1 and R 2 from the viewpoint of suppressing RyR2 activity, substituted or unsubstituted alkyl groups having 1 to 8 carbon atoms, substituted or unsubstituted alkoxy groups having 2 to 8 carbon atoms, substituted or unsubstituted carbons.
  • Alkoxy groups of numbers 1 to 8, substituted or unsubstituted alkoxycarbonyl groups of 2 to 8 carbon atoms, hydroxy groups, cyano groups, or halogen atoms are preferable, and substituted or unsubstituted alkyl groups of 1 to 8 carbon atoms are substituted.
  • an unsubstituted or unsubstituted alkenyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a cyano group, or a halogen atom may be used.
  • a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a cyano group, or a halogen.
  • Atoms are more preferred, substituted or unsubstituted alkoxy groups having 1 to 8 carbon atoms, or halogen atoms are even more preferred, and halogen atoms are particularly preferred.
  • the substitution position of R 1 may be any on the ring Q 1, but from the viewpoint of RyR2 activity inhibiting effect, if and n ring Q 1 is a benzene ring is an integer of 1 ⁇ 5, R 1 is at least It is preferable to replace it with the 3-position.
  • the substitution position of R 2 may be any on ring Q 2 but, from the viewpoint of RyR2 activity inhibiting effect, the ring Q 2 is a benzene ring and when m is an integer of 1 ⁇ 5, R 2 is at least 4-position It is preferable to replace with.
  • R 3 from the viewpoint of the effect of suppressing RyR2 activity, a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms, or a substituted or unsubstituted alkenyl group having 2 to 8 carbon atoms is preferable, and the hydrogen atom, Alternatively, a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms is more preferable, a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms is further preferable, and a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms is further preferable. Preferably, a methyl group is particularly preferred.
  • R 4 represents a divalent hydrocarbon group having 1 to 8 carbon atoms.
  • the divalent hydrocarbon group represented by R 4 is a concept including a divalent aliphatic hydrocarbon group, a divalent alicyclic hydrocarbon group, and a divalent aromatic hydrocarbon group. Valuable aliphatic hydrocarbon groups are preferred.
  • the divalent aliphatic hydrocarbon group may be linear or branched chain, and may be saturated or unsaturated. Examples of the divalent aliphatic hydrocarbon group include an alkanediyl group, an alkendyl group, and an alkindiyl group.
  • an alkanediyl group and an alkanediyl group are preferable, and an alkanediyl group is more preferable, from the viewpoint of the effect of suppressing RyR2 activity.
  • the carbon number of the alkanediyl group is preferably 1 to 8, more preferably 1 to 4, still more preferably 1 to 3, and particularly preferably 1 from the viewpoint of the effect of suppressing RyR2 activity.
  • Examples of the alkanediyl group include methane-1,1-diyl group, ethane-1,1-diyl group, ethane-1,2-diyl group, propane-1,1-diyl group, and propane-1,2-.
  • Diyl group propane-1,3-diyl group, propane-2,2-diyl group, butane-1,1-diyl group, butane-1,2-diyl group, butane-1,3-diyl group, butane- 1,4-diyl group, pentane-1,4-diyl group, pentane-1,5-diyl group, hexane-1,2-diyl group, hexane-1,5-diyl group, hexane-1,6-diyl
  • Examples include groups, heptan-1,7-diyl groups, octane-1,8-diyl groups and the like.
  • a methane-1,1-diyl group is preferable from the viewpoint of suppressing RyR2 activity.
  • the number of carbon atoms of the arcendyl group and the alkindiyl group is preferably 2 to 8, more preferably 2 to 4, and particularly preferably 2 to 3.
  • Examples of the alkenyl group include an ethylene-1,1-diyl group and an ethylene-1,2-diyl group.
  • Examples of the alkyndiyl group include an acetylene-1,2-diyl group and the like.
  • n and m each independently represent an integer of 0 to 5, but from the viewpoint of the effect of suppressing RyR2 activity, an integer of 1 to 5 is preferable, and an integer of 1 to 3 is more preferable. An integer of 1 to 2 is particularly preferable.
  • n and m in the formula ( ⁇ 2) are preferably integers of 1 to 3 and more preferably integers of 1 to 2 from the viewpoint of the effect of suppressing RyR2 activity.
  • the compounds ( ⁇ 1) to ( ⁇ 12) include salts of the compounds represented by the formulas ( ⁇ 1) to ( ⁇ 12), and the salts include, for example, alkali metals such as sodium salt and potassium salt. Salts; salts with metals of Group 2 elements such as calcium salts and magnesium salts; salts with metals of Group 13 elements such as aluminum salts; ammonium salts; organic amine salts such as phenethylamine salts and the like.
  • examples of the solvate include a hydrate and an alcohol solvate.
  • the compounds ( ⁇ 1) to ( ⁇ 12) may have polymorphs of crystals, but they may be in a single crystalline form or a mixture of a plurality of crystalline forms. Further, it may be in an amorphous form.
  • the compound ( ⁇ 2) is a compound in which n and m represent integers of 1 to 5 among the compounds ( ⁇ 1).
  • the compound represented by the formula ( ⁇ 3) is the compound 39 of the following example, and the compound represented by the formula ( ⁇ 4) is the compound 44 of the following example, which is represented by the formula ( ⁇ 5).
  • the compound is the compound 61 of the following example, the compound represented by the formula ( ⁇ 6) is the compound 66 of the following example, and the compound represented by the formula ( ⁇ 7) is the compound 40 of the following example.
  • the compound represented by the formula ( ⁇ 8) is the compound 38 of the following example, and the compound represented by the formula ( ⁇ 9) is the compound 59 of the following example, which is represented by the formula ( ⁇ 10).
  • the compound is the compound 47 of the following example, the compound represented by the formula ( ⁇ 11) is the compound 37 of the following example, and the compound represented by the formula ( ⁇ 12) is the compound 41 of the following example. be.
  • the compound ( ⁇ 1) uses NT Pokhodylo, RD Savka, VS Matiichuk, and ND Obushak, A Study of Alkylation Regioselectivity of 5-Substituted Tetrazoles with ⁇ hloroacetamides using a nitrile compound (CP1) or bromocarboxylic acid (CP6) as a starting material. It can be produced by appropriately combining known methods described in. Russian Journal of General Chemistry, 80, 836-841 (2010). Etc.
  • R 3 in the formula ( ⁇ 1) is a hydrocarbon group. You can get things. Further, by reacting a compound (CP5), a compound (CP11), or a compound obtained by reacting these with a hydrocarbon iodide with a sulfide agent such as Lawesson's reagent, X in the formula ( ⁇ 1) is a sulfur atom. You can get what is.
  • the compound represented by the formula ( ⁇ 1) or a salt thereof or a solvate thereof, which can be produced as described above, has an excellent effect of suppressing RyR2 activity and prevents diseases related to abnormal enhancement of RyR2 activity. Or it is useful as a therapeutic agent.
  • the disease associated with the abnormal increase in RyR2 activity may be a disease caused by a mutation in RyR2 (specifically, an increase in activity type mutation) or a disease related to an abnormal increase in wild-type RyR2 activity, and may be, for example, arrhythmia or heart failure. , Cardiomyopathy, neurological disease, Alzheimer's disease.
  • Diseases caused by hyperactive mutations in RyR2 include, specifically, catecholamine-induced polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, arrhythmogenic right ventricular cardiomyopathy, left ventricular densification disorder, epilepsy, etc.
  • Mental retardation can be mentioned.
  • Specific examples of the disease related to the abnormal increase in wild-type RyR2 activity include chronic heart failure and Alzheimer's disease accompanied by sympathetic tone in wild-type RyR2.
  • the compound ( ⁇ 1) of the present invention is derived from catecholamine-induced polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, arrhythmogenic right ventricular cardiomyopathy, left ventricular densification disorder, epilepsy, mental retardation, chronic heart failure and Alzheimer's disease. It is particularly useful as a prophylactic or therapeutic agent for selected diseases.
  • the compound ( ⁇ 1) of the present invention can be a RyR2 activity inhibitor, a drug for the prevention or treatment of diseases related to abnormal increase in RyR2 activity, and prevention of diseases related to suppression of RyR2 activity and abnormal increase in RyR2 activity.
  • it can be used for treatment, and can also be used for producing a RyR2 activity inhibitor, a drug for preventing or treating a disease associated with an abnormal increase in RyR2 activity.
  • the above-mentioned "use” may be administration or ingestion to human or non-human animals.
  • the RyR2 activity inhibitor and the pharmaceutical application means of the present invention may be either parenteral or oral such as injection, transrectal and topical administration.
  • a pharmaceutically acceptable carrier may be combined with the compound ( ⁇ 1) of the present invention to prepare a pharmaceutical composition.
  • known ones such as excipients, binders, buffers, thickeners, stabilizers, emulsifiers, dispersants, suspending agents and preservatives may be used. It can be formulated by a usual method.
  • Examples of the orally-administered preparation include tablets (including sugar-coated tablets, film-coated tablets, etc.), pills, granules, powders, capsules (including soft capsules, etc.), syrups, emulsions, suspensions, and the like. Be done.
  • the orally-administered preparation can be produced according to a known method using additives usually used in the preparation field. Examples of such additives include excipients such as lactose, mannitol and anhydrous calcium hydrogen phosphate; binders such as hydroxypropyl cellulose, methyl cellulose and polyvinylpyrrolidone; disintegrants such as starch and carboxymethyl cellulose; magnesium stearate. , Talc and other lubricants.
  • parenteral-administered preparation examples include an injection, a rectal-administered preparation, and a locally-administered preparation. Of these, injections are preferred.
  • the injection examples include a sterile solution or suspension of the compound ( ⁇ 1) of the present invention.
  • a sterile solution or suspension of the compound ( ⁇ 1) of the present invention can be produced by dissolving or suspending the compound ( ⁇ 1) of the present invention in Japanese Pharmacopoeia water for injection.
  • the injection may contain an isotonic agent such as sodium chloride; a buffer such as sodium dihydrogen phosphate or sodium monohydrogen phosphate; a solubilizing agent or the like. It can also be used as a dissolution-type (powder-filled, freeze-dried) injection, and in this case, it can be produced by a usual method by adding excipients such as mannitol and lactose.
  • rectal-administered preparation examples include suppositories and the like.
  • the suppository can be produced, for example, by dissolving or suspending the compound ( ⁇ 1) of the present invention in a base such as cacao fat or macrogol, and then pouring it into a mold to form a suppository.
  • the liquid or cream can be placed in a container for injection to prepare a rectal-administered preparation.
  • Examples of the dosage form of the topically administered preparation include liquid preparations, eye drops, creams, ointments, gel preparations, sprays, powders and the like.
  • the liquid preparation can be produced by adding the compound ( ⁇ 1) of the present invention to water and adding a stabilizer, a solubilizer, a thickener, a dispersant, a suspending agent and the like as necessary.
  • the eye drops can be produced, for example, by adding a preservative in addition to the compound ( ⁇ 1) of the present invention, a buffer, a pH adjuster, and an isotonic agent.
  • Creams and ointments are produced, for example, by using an aqueous or oily base (for example, water, liquid paraffin, vegetable oil (peanut oil, castor oil, etc.), macrogol, etc.) together with the compound ( ⁇ 1) of the present invention.
  • the gel preparation includes, for example, gelatin, pectin, carrageenan, agar, tragant, alginate, cellulose ether (methyl cellulose, sodium carboxymethyl cellulose, etc.), pectin derivative, polyacrylate, polymethacrylate, polyvinyl alcohol, together with the compound ( ⁇ 1) of the present invention.
  • Polyvinylpyrrolidone and the like can be used.
  • the spray agent can be produced by dissolving or suspending the compound ( ⁇ 1) of the present invention in water or the like and then putting it in a spray container.
  • the compound ( ⁇ 1) of the present invention can be used as it is, but it may be produced by mixing it with an appropriate excipient.
  • the dose or intake of the RyR2 activity inhibitor and the drug of the present invention is determined in consideration of the target disease or symptom, the age, body weight, gender, etc. of the target.
  • the amount of the compound ( ⁇ 1) of the present invention is usually 0.01 to 100 mg, preferably 0.01 to 30 mg, and more preferably 0.1 to 10 mg per day for an adult (body weight of about 60 kg). This is administered or ingested once or in 2 to 4 divided doses.
  • the daily dose for an adult is usually 0.03 to 3000 ⁇ g, preferably 0.03 to 300 ⁇ g, more preferably 0. as the compound ( ⁇ 1) of the present invention per 1 kg of body weight. It is 03 to 30 ⁇ g and is administered once to multiple times a day.
  • the 1 H NMR spectrum was measured using an AVANCE 400 or AVANCE 500 spectrometer manufactured by Bruker.
  • the electrocardiogram was continuously monitored. After monitoring for 10 minutes before drug administration, the compound 57-containing solution was injected intraperitoneally to 0.3 mg / kg or 1 mg / kg, and an electrocardiogram was recorded for another 15 minutes.
  • the results of intraperitoneal injection of 0.3 mg / kg are shown in FIG.
  • bidirectional ventricular tachycardia occurred periodically before the administration of the compound 57, but the ECG returned to normal by the intraperitoneal administration of the compound 57 at 0.3 mg / kg.
  • (4) Results and discussion After administration of Compound 57, the time during which continuous 2-step pulse, 3-step pulse or ventricular tachycardia occurred for 5 to 15 minutes was counted as arrhythmia for each individual, and arrhythmia occurred. The percentage of time was calculated. The results are shown in FIG. From the results shown in FIG. 2, it can be seen that when the compound 57 is administered at 0.3 mg / kg or 1 mg / kg, arrhythmia is less likely to occur.

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Abstract

Le but de la présente invention est de fournir un inhibiteur de l'activité du récepteur de la ryanodine de type 2 (RyR2) ayant un excellent effet d'inhibition de l'activité de RyR2.　Un inhibiteur de l'activité de RyR2 comprend un composé représenté par une formule (α1), un sel de celui-ci ou un solvate de celui-ci. [Dans la formule (α1) ; les cycles Q1 et Q2 représentent indépendamment un hétérocycle monocyclique, un cycle condensé d'un cycle de carbone monocyclique avec un cycle benzène, ou un cycle benzène ; R1 et R2 représentent indépendamment un groupe hydrocarboné éventuellement substitué ayant entre 1 et 8 atomes de carbone, un groupe alcoxy éventuellement substitué ayant entre 1 et 8 atomes de carbone, un groupe alcoxycarbonyle éventuellement substitué ayant entre 2 et 8 atomes de carbone, un groupe alcanoyle éventuellement substitué ayant entre 2 et 8 atomes de carbone, un groupe alcanoyloxy éventuellement substitué ayant entre 2 et 8 atomes de carbone, un groupe hydroxy, un groupe cyano ou un atome d'halogène ; R3 représente un atome d'hydrogène ou un groupe hydrocarboné éventuellement substitué ayant entre 1 et 8 atomes de carbone ; R4 représente un groupe hydrocarboné divalent ayant entre 1 et 8 atomes de carbone ; X représente un atome d'oxygène ou un atome de soufre ; Y représente un groupe méthine ou un atome d'azote ; et n et m représentent indépendamment un nombre entier compris entre 0 et 5.　Lorsque n est un nombre entier compris entre 2 et 5, alors n R1 peuvent être identiques ou différents et deux R1 peuvent former ensemble un cycle. Lorsque m est un nombre entier compris entre 2 et 5, alors m R2 peuvent être identiques ou différents et deux R2 peuvent former ensemble un cycle.]
PCT/JP2021/005044 2020-02-10 2021-02-10 Inhibiteur de l'activité du récepteur de la ryanodine de type 2 WO2021162054A1 (fr)

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US20230150952A1 (en) 2023-05-18
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